Mechanisms underlying the prokinetic effects of endogenous glucagon-like peptide-1 in the rat proximal colon.

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  • Author(s): Nakamori H;Nakamori H; Iida K; Iida K; Hashitani H; Hashitani H
  • Source:
    American journal of physiology. Gastrointestinal and liver physiology [Am J Physiol Gastrointest Liver Physiol] 2021 Dec 01; Vol. 321 (6), pp. G617-G627. Date of Electronic Publication: 2021 Oct 13.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: American Physiological Society Country of Publication: United States NLM ID: 100901227 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-1547 (Electronic) Linking ISSN: 01931857 NLM ISO Abbreviation: Am J Physiol Gastrointest Liver Physiol Subsets: MEDLINE
    • Publication Information:
      Original Publication: Bethesda, MD : American Physiological Society
    • Subject Terms:
      Gastrointestinal Motility*/drug effects; Colon/*metabolism ; Enteroendocrine Cells/*metabolism ; Glucagon-Like Peptide 1/*metabolism ; Glucagon-Like Peptide-1 Receptor/*metabolism; Animals ; Calcitonin Gene-Related Peptide/metabolism ; Colon/drug effects ; Colon/innervation ; Enteric Nervous System/drug effects ; Enteric Nervous System/metabolism ; Fatty Acids/pharmacology ; Glucagon-Like Peptide 1/pharmacology ; Glucagon-Like Peptide-1 Receptor/agonists ; Glucagon-Like Peptide-1 Receptor/antagonists & inhibitors ; In Vitro Techniques ; Male ; Peptide Fragments/pharmacology ; Peptides/pharmacology ; Rats, Wistar ; Rats
    • Abstract:
      Glucagon-like peptide-1 (GLP-1), a well-known insulin secretagogue, is released from enteroendocrine L cells both luminally and basolaterally to exert different effects. Basolaterally released GLP-1 increases epithelial ion transport by activating CGRP-containing enteric afferent neurons. Although bath-applied GLP-1 reduced the contractility of colonic segments, GLP-1-induced stimulation of afferent neurons could also accelerate peristaltic contractions. Here, the roles of endogenous GLP-1 in regulating colonic peristalsis were investigated using isolated colonic segments. Isolated segments of rat proximal colon were placed in an organ bath, serosally perfused with oxygenated physiological salt solution, and luminally perfused with degassed 0.9% saline. Colonic wall motion was recorded using a video camera and converted into spatiotemporal maps. Intraluminal administration of GLP-1 (100 nM) stimulating the secretion of GLP-1 from L cells increased the frequency of oro-aboral propagating peristaltic contractions. The acceleratory effect of GLP-1 was blocked by luminally applied exendin-3 (9-39) (100 nM), a GLP-1 receptor antagonist. GLP-1-induced acceleration of peristaltic contractions was also prevented by bath-applied BIBN4069 (1 μM), a CGRP receptor antagonist. In colonic segments that had been exposed to bath-applied capsaicin (100 nM) that desensitizes extrinsic afferents, GLP-1 was still capable of exerting its prokinetic effect. Stimulation of endogenous GLP-1 secretion with a luminally applied cocktail of short-chain fatty acids (1 mM) increased the frequency of peristaltic waves in an exendin-3 (9-39)-sensitive manner. Thus, GLP-1 activates CGRP-expressing intrinsic afferents to accelerate peristalsis in the proximal colon. Short-chain fatty acids appear to stimulate endogenous GLP-1 secretion from L cells resulting in the acceleration of colonic peristalsis. NEW & NOTEWORTHY Glucagon-like peptide-1 (GLP-1) activates CGRP-containing intrinsic afferent neurons resulting in the acceleration of colonic peristalsis. Short-chain fatty acids stimulate the secretion of endogenous GLP-1 from L cells that accelerates colonic peristalsis. Thus, besides the well-known humoral insulinotropic action, GLP-1 exerts a local action via the activation of the enteric nervous system to accelerate colonic motility. Such a prokinetic action of GLP-1 could underlie the mechanisms causing diarrhea in patients with type-2 diabetes treated with GLP-1 analogs.
    • Contributed Indexing:
      Keywords: enteric nervous system; gastrointestinal motility; glucagon-like peptide-1; peristalsis; short-chain fatty acid
    • Accession Number:
      0 (Fatty Acids)
      0 (Glp1r protein, rat)
      0 (Glucagon-Like Peptide-1 Receptor)
      0 (Peptide Fragments)
      0 (Peptides)
      130391-54-7 (exendin 3)
      5313W10MYT (exendin (9-39))
      89750-14-1 (Glucagon-Like Peptide 1)
      JHB2QIZ69Z (Calcitonin Gene-Related Peptide)
    • Publication Date:
      Date Created: 20211013 Date Completed: 20211206 Latest Revision: 20240226
    • Publication Date:
      20240226
    • Accession Number:
      10.1152/ajpgi.00175.2021
    • Accession Number:
      34643099